Acceleration of type 1 diabetes by a coxsackievirus infection requires a preexisting critical mass of autoreactive T-cells in pancreatic islets.

Abstract

Coxsackievirus infections have been proposed as an environmental trigger for the development of T-cell-mediated autoimmune (type 1) diabetes by either providing a molecular mimic of the candidate pancreatic ␤-cell autoantigen GAD or inducing bystander inflammation in the pancreas. In this study in the NOD mouse model, we found that infection with a pancreatrophic coxsackievirus isolate can accelerate type 1 diabetes development through the induction of a bystander activation effect, but only after a critical threshold level of insulitic ␤-cell-autoreactive T-cells has accumulated. Thus, coxsackievirus infections do not appear to initiate ␤-cell autoreactive immunity but can accelerate the process once it is underway. These findings indicate that the timing of a coxsackievirus infection, rather than its simple presence or absence, may have important etiological implications for the development of T-cell-mediated autoimmune type 1 diabetes in humans. Diabetes 49:708-711, 2000 T -cell-mediated autoimmune (type 1) diabetes in both humans and NOD mice is controlled by multiple susceptibility genes whose pathogenic functions can be modulated by various environmental factors (1-3). Coxsackieviral infections may represent one environmental factor that could contribute to type 1 diabetes development in genetically susceptible individuals (4). An antigenic epitope derived from the 65-and 67-kDa isoforms of GAD and proposed to be one of the earliest targets of diabetogenic CD4 + T-cell responses in NOD mice is characterized by a PEVKEK sequence also found within a peptide consisting of amino acids 28-50 from the coxsackievirus P2C protein (Cox sequence similarity peptide [ssp]) (5). Thus, one mechanism by which a coxsackievirus infection could contribute to type 1 diabetes is by providing a molecular mimic during replication that triggers a cross-reactive CD4 + T-cell response against the candidate ␤-cell autoantigen GAD. Arguing against this molecular mimicry hypothesis was a report that GAD reactive T-cell responses were not enhanced in NOD mice after a coxsackievirus infection (6). Instead, this earlier study found that the coxsackievirus B4 Edwards strain (CVB4) can accelerate type 1 diabetes development in a T-cell receptor (TCR) transgenic stock of NOD mice in which virtually all T-cells are of the CD4 + BDC2.5 clonotype that recognizes a ␤-cell autoantigen other than GAD. This finding was interpreted to mean that rather than providing a molecular mimic of GAD, infection with the pancreatrophic CVB4 isolate contributes to type 1 diabetes development by stimulating a local inflammatory response that leads to subclinical levels of ␤-cell destruction and the subsequent release of normally sequestered antigens, which then trigger pathogenic autoreactive T-cell responses. However, this interpretation does not explain why, in that previous study, CVB4 infection failed to elicit type 1 diabetes development in standard nontransgenic NOD mice that are characterized by not only the presence of BDC2.5 clonotypic T-cells, but al...

Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice

“…Diabetes development after enterovirus infection in the most commonly used experimental model, the NOD mouse, is dependent on the already established prediabetic phase including insulitis [15][16][17]31], which in the NOD mouse occurs after maternally transferred antibodies may have waned [32]. This is in contrast with humans in whom islet autoantibodies may already appear before the disappearance of maternal antibodies [23,33,34].…”

“…[6,12]). Furthermore, experimental animal models have indicated that enterovirus infections can cause direct beta cell damage [13,14] and alter disease progression in the NOD mouse model [15][16][17].…”

Restricted TCR Vβ gene expression and enterovirus infection in Type I diabetes: a pilot study

“…It has been shown that the timing of a Coxsackievirus infection, rather than a simple documentation of its presence or absence, has important implications in the development of diabetes in NOD mice. In this animal model, CVB4 infection can accelerate the development of Type I diabetes only after a critical amount of autoreactive T cells have accumulated at the periphery of the islets [32]. Based on this finding, we suppose that in humans, like in rodents, the timing of a Coxsackievirus infection is a critical factor in the development of diabetes by activating autoreactive T cells already present in the circulation and possibly in proximity to the islets.…”

Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference?

“…53 The observed exacerbation of T1D requires both uptake and activation of antigen-presenting cells 54 as well as presence of a pre-existing critical mass of autoreactive T cells within the islets of Langerhans. 55 This later observation is intriguing since it demonstrates that CVB4 might rather accelerate an ongoing autodestructive process than de novo induce T1D. It is interesting to note that even infection of regular wild-type mice with CVB4 causes insulitis, low serum insulin levels and moderately elevated blood glucose values.…”